The efforts of this section are directed at understanding the early events in the interaction of phorbol ester tumor promoters with cells and tissues. To characterize the phorbol ester receptor biochemically we have prepared photoaffinity labels and affinity columns. The photoaffinity labeling studies in brain suggest that the receptor is a lipoprotein, with phosphatidylserine and phosphatidylethanolamine in proximity to the ligand binding site. The subdivision of promotion into multiple stages implies the existence of subclasses of receptors. In fact, we have been able to demonstrate three subclasses of phorbol ester receptors with distinct structure-activity requirements in mouse skin homogenates. As part of a genetic analysis of receptors, we have screened cultured mouse cells and nematode variants altered in their responsiveness to the phorbol esters. All variants so far are altered at steps distal to ligand binding. During assays for possible endogenous ligands in brain acting at the phorbol esters receptor, ascorbic acid was the major inhibitor detected. Its inhibition, however, was irreversible, being mediated through induction of lipid peroxidation.